The Identification and Characterization of a STAT 1 Binding Site in the PPARγ2 Promoter

Hogan, Jessica C.; Stephens, Jacqueline M.

doi:10.1006/bbrc.2001.5606

Cited by 31 publications

(21 citation statements)

References 38 publications

(46 reference statements)

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“…(33), also resulted in binding competition. However, binding was not competed with a STAT1 binding site that is present at Ϫ221 to Ϫ207 of the peroxisome proliferatoractivated receptor ␥2 promoter (34). To determine whether the protein complex binding the Ϫ908 to Ϫ893 contained STAT proteins, we performed supershift analysis using antibodies directed against the STAT proteins expressed in adipocytes.…”

Section: Stat5a Represses Fas In Adipocytesmentioning

confidence: 99%

The Regulation of Fatty Acid Synthase by STAT5A

Hogan

Stephens

2005

Diabetes

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Growth hormone (GH) diminishes adipose tissue mass in vivo and decreases expression and activity of fatty acid synthase (FAS) in adipocytes. GH and prolactin (PRL) are potent activators of STAT5 and exert adipogenic and antiadipogenic effects in adipocytes. In this study, we demonstrate that GH and PRL decrease the mRNA and protein levels of FAS in 3T3-L1 adipocytes. We present evidence that indicates that FAS is repressed at the level of transcription. In addition, PRL responsiveness was shown to exist between ؊1,594 and ؊700 of the rat FAS promoter. Moreover, responsiveness to PRL was abolished with mutation of a site at position ؊908 to ؊893, which we have shown to bind STAT5A in a PRL-dependent manner. Taken together, these data strongly suggest that PRL directly represses expression of FAS in adipocytes through STAT5A binding to the ؊908 to ؊893 site. Furthermore, our results indicate that STAT5A has an antilipogenic function in adipocytes and may contribute to the regulation of energy balance.

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Section: Stat5a Represses Fas In Adipocytesmentioning

confidence: 99%

The Regulation of Fatty Acid Synthase by STAT5A

Hogan

Stephens

2005

Diabetes

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“…Previous work from our laboratory has shown that downregulation of PPAR␥ by interferon-␥ can occur at the level of transcription and may be mediated by STAT1 binding to the Ϫ221 to Ϫ207 element of the PPAR␥2 promoter (26). Therefore, we examined the ability of CT-1-activated STAT1 proteins to bind the Ϫ221 to Ϫ207 element of the PPAR␥2 promoter.…”

Section: Ct-1 Signaling In Adipocytesmentioning

confidence: 99%

Effects of Cardiotrophin on Adipocytes

Zvonic

Hogan

Arbour-Reily

et al. 2004

Journal of Biological Chemistry

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Cardiotrophin (CT-1) is a naturally occurring protein member of the interleukin (IL)-6 cytokine family and signals through the gp130/leukemia inhibitory factor receptor (LIFR) heterodimer. The formation of gp130/ LIFR complex triggers the auto/trans-phosphorylation of associated Janus kinases, leading to the activation of Janus kinase/STAT and MAPK (ERK1 and -2) signaling pathways. Since adipocytes express both gp130 and LIFR proteins and are responsive to other IL-6 family cytokines, we examined the effects of CT-1 on 3T3-L1 adipocytes. Our studies have shown that CT-1 administration results in a dose-and time-dependent activation and nuclear translocation of STAT1, -3, -5A, and -5B as well as ERK1 and -2. We also confirmed the ability of CT-1 to induce signaling in fat cells in vivo. Our studies revealed that neither CT-1 nor ciliary neurotrophic factor treatment affected adipocyte differentiation. However, acute CT-1 treatment caused an increase in SOCS-3 mRNA in adipocytes and a transient decrease in peroxisome proliferator-activated receptor ␥ (PPAR␥) mRNA that was regulated by the binding of STAT1 to the PPAR␥2 promoter. The effects of CT-1 on SOCS-3 and PPAR␥ mRNA were independent of MAPK activation. Chronic administration of CT-1 to 3T3-L1 adipocytes resulted in a decrease of both fatty acid synthase and insulin receptor substrate-1 protein expression yet did not effect the expression of a variety of other adipocyte proteins. Moreover, chronic CT-1 treatment resulted in the development of insulin resistance as judged by a decrease in insulin-stimulated glucose uptake. In summary, CT-1 is a potent regulator of signaling in adipocytes in vitro and in vivo, and our current efforts are focused on determining the role of this cardioprotective cytokine on adipocyte physiology.

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“…STAT5 positively regulates expression of PPAR␥ during the initial phase of 3T3-L1 cell differentiation (Nanbu-Wakao et al, 2002). In contrast, STAT1 binds to regulatory sequences upstream of the PPAR␥ gene in 3T3-L1 cells, negatively regulating PPAR␥ protein expression, leading to a decrease in the activation in PPAR␥-regulated genes (Hogan and Stephens, 2001). STAT1 is positively regulated by PPAR␥ in NIH-3T3 fibroblasts, with a differentiation-dependent up-regulation of STAT1 protein occurring downstream of PPAR␥ in a ligand-dependent manner (Stephens et al, 1999).…”

Section: Stat5b-ppar Inhibitory Cross-talk 361mentioning

confidence: 99%

“…Inhibition of STAT1-regulated transcription by PPAR␥ occurs in HeLa cells (Ricote et al, 1998), although not in COS-1 cells (this report). STAT1 can decrease PPAR␥-regulated gene transcription indirectly, by binding upstream of, and repressing transcription of the PPAR␥ gene, leading to decreased PPAR␥ protein expression (Hogan and Stephens, 2001). STAT5 transcriptional activity is strongly inhibited by the estrogen receptor (ER) via mechanisms that involve a direct interaction between the receptor and STAT5 (Faulds et al, 2001) and via an indirect inhibitory effect of ER on STAT5 activation and nuclear localization (Sueyoshi et al, 1999).…”

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confidence: 99%

Down-Regulation of STAT5b Transcriptional Activity by Ligand-Activated Peroxisome Proliferator-Activated Receptor (PPAR) α and PPARγ

Shipley¹,

Waxman²

2003

Mol Pharmacol

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The nuclear receptor peroxisome proliferator-activated receptor (PPAR) is activated by a diverse group of acidic ligands, including many peroxisome proliferator chemicals present in the environment. Janus tyrosine kinase-signal transducer and activator of transcription (JAK-STAT) signaling is activated by multiple cytokines and hormones and leads to the translocation of dimerized STAT proteins to the nucleus where they activate transcription of target genes. Previous studies have shown that growth hormone (GH)-activated STAT5b can inhibit PPAR-regulated transcription. Here, we show that this inhibitory crosstalk is mutual, and that GH-induced, STAT5b-dependent ␤-casein promoter-luciferase reporter gene transcription can be inhibited up to ϳ80% by ligand-activated PPAR␣ or PPAR␥. Dose-response experiments showed a direct relationship between the extent of PPAR activation and the degree of inhibition of STAT5-regulated transcription. PPAR did not block STAT5b tyrosine phosphorylation or inhibit DNA-binding activity. Both PPARs inhibited the transcriptional activity of a constitutively active STAT5b mutant, indicating that inhibition occurs downstream of the GH-stimulated STAT5 activation step. Transcriptionally inactive, dominant-negative PPAR mutants did not block STAT5b inhibition by wild-type PPAR, indicating that PPAR target gene transcription is not required. PPAR␣ retained its STAT5b inhibitory activity in the presence of the histone deacetylase inhibitor trichostatin, indicating that enhanced histone deacetylase recruitment does not contribute to STAT5b inhibition. PPAR␣ lacking the ligand-independent AF-1 trans-activation domain failed to inhibit STAT5b, highlighting the importance of the AF-1 region in STAT5-PPAR inhibitory cross-talk. These findings demonstrate the bidirectionality of cross-talk between the PPAR and STAT pathways and provide a mechanism whereby exposure to environmental chemical activators of PPAR can suppress expression of GH target genes.

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The Identification and Characterization of a STAT 1 Binding Site in the PPARγ2 Promoter

Cited by 31 publications

References 38 publications

The Regulation of Fatty Acid Synthase by STAT5A

The Regulation of Fatty Acid Synthase by STAT5A

Effects of Cardiotrophin on Adipocytes

Down-Regulation of STAT5b Transcriptional Activity by Ligand-Activated Peroxisome Proliferator-Activated Receptor (PPAR) α and PPARγ

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